1. Field of Invention
This invention relates to the stabilization of acetylsalicyclic acid in the presence of d-propoxyphene hydrochloride in pharmaceutical compositions. Specifically, it relates to the inhibition of the hydrolysis of said acetylsalicyclic acid in such compositions.
2. Description of the Prior Art
Combinations of therapeutic agents to provide single unit dosage forms which are convenient for administering pharmaceutical compositions containing more than one active agent in a single dose are old in the pharmaceutical art, and many of these contain, among other ingredients, acetylsalicylic acid. Acetylsalicylic acid, hereinafter referred to as aspirin, is an analgesic of unquestioned merit employed around the world for the alleviation of pain associated with simple headaches, neuralgia, neuritis, rheumatism, and assorted other afflications of the body. Aspirin is a common ingredient in pharmaceutical dosage forms containing combinations of analgesic agents, and these combinations have been utilized for decades to improve the scope of analgesic therapy.
Aspirin is odorless and in the dry state is stable, but in the presence of moisture slowly hydrolyzes into acetic and salicylic acids and takes on the characteristic odor of acetic acid. In pharmaceutical compositions, even a small amount of aspirin hydrolysis is sufficient to product the disagreeably pungent odor of acetic acid and destroy the pharmaceutical elegance and patient acceptability of the composition. A free salicylic acid content of more than 3 percent exceeds the USP XVIII (1970) standard, and renders the composition containing aspirin unsaleable.
The analgesic d-propoxyphene hydrochloride, U.S. Pat. No. 2,728,779 (1955), has gained wide acceptance as a drug for the treatment of pain associated with traumas, particularly since it is not addictive. The combination of aspirin, d-propoxyphene hydrochloride, phenacetin and caffeine has been sold throughout most of the world for more than a decade, and has become established as a superior treatment for many uncomplicated manifestations of pain.
Pharmaceutical compositions comprising aspirin and d-propoxyphene hydrochloride, with and without other ingredients in combination therewith, especially those which have been filled into gelatin capsules to provide a unit dosage form, have been particularly susceptible to the hydrolysis of the aspirin and the concomitant development of the pungent odor of acetic acid, thus making the pharmaceutical form totally unacceptable to the patient. One such multiple component pharmaceutical composition is constituted as follows: aspirin, 40.0 percent; d-propoxyphene hydrochloride, 11.4 percent; phenacetin, 28.4 percent; caffeine, 5.7 percent; and starch, 14.5 percent. Another is constituted simply of aspirin, 52.4 percent; d-propoxyphene hydrochloride, 10.5 percent; and kaolin, 37.1 percent. Still another is composed of aspirin, 58.0 percent; d-propoxyphene hydrochloride, 5.7 percent, phenaglycodol, 26.8 percent; and silica gel, 9.5 percent.
In the pharmaceutical compositions illustrated above, the common denominator is the combination of aspirin and de-propoxyphene hydrochloride. The commingling of d-propoxyphene hydrochloride with aspirin in pharmaceutical compositions has uniformly resulted in an increase in both the rate and amount of aspirin hydrolysis. The exact reason for this phenomenon is not completely understood. Several attempts have been made to overcome the hydrolysis problem, notably by forming a small tablet or nonpareil type pellet of d-propoxyphene hydrochloride to isolate the latter from the aspirin or by the coacervate coating of the aspirin with ethyl cellulose to segregate it from the d-propoxyphene hydrochloride. Neither approach entirely corrects the difficulty. An effective method for inhibiting the hydrolysis of aspirin in the presence of d-propoxyphene hydrochloride in pharmaceutical compositions would, therefore, constitute a much-needed advance in the art.